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Diabetes

Diabetes

Diabetes

Description
 Diabetes means that your blood glucose (sugar) is too high. Your blood always has some glucose in it because the body needs glucose for energy to keep you going. Too much glucose in the blood is not good for your health. Diabetes is a silent disease. You could have it for years and never know it. During this time, your eyes, nerves, and kidneys may have been harmed by too much sugar in the blood.

Who is at Risk?
 Your risk for diabetes increases as you get older, gain too much weight, or if you do not stay active. Diabetes is more common in African Americans, Latinos, Native Americans, Asian Americans and Pacific Islanders. Risk factors for diabetes include having high blood pressure (at or above 130/80), having a family history of diabetes, and having diabetes during pregnancy or having a baby weighing more than nine pounds at birth.

Source: American Diabetes Association

Curtailing the Development of Diabetes
 TSRI scientists are proposing a new hypothesis about the cause of autoimmunity, in which components of a person"s immune system attack his/her own tissues leading to diseases such as Type 1 diabetes and rheumatoid arthritis. While autoimmunity has traditionally been considered a condition of too much stimulation, the scientists led by TSRI Professor Nora Sarvetnick, Ph.D. saw a condition of not enough stimulation to fill the body with immune cells, resulting in too few T cells. The hypothesis provides a new way of thinking about how to make autoimmune diseases more preventable through stimulating the immune system by priming people with germs.

Type 1 (insulin-dependent) diabetes mellitus manifests when T cells become autoreactive and attack and kill beta cells in the pancreas, the body"s source of insulin. Without insulin, the glucose in the bloodstream increases and is maintained at levels much greater than normal. Over time, this can lead to nerve and kidney damage, reduced eyesight, and an increased risk of developing heart disease and vascular degeneration. Insulin is a reasonable treatment, but Type1 diabetes is still a chronic infection for which there is no prevention and no cure. In the study, Sarvetnick and her colleagues look at the immune systems of a type of mouse called NOD, which is genetically prone to developing diabetes. The researchers infused and passively stimulated the immune systems of NOD mice with T cells, which prevented the NOD mice from developing diabetes.

This project is part of a program focusing on the basic mechanisms of autoimmunity that combines the research interests of Sarvetnick, Professor Linda Sherman, Ph.D., and Associate Professor Sue Webb, Ph.D. The program project grant funds studies in all three labs that focus on the specific goal of better understanding how the immune system goes awry in the development of Type 1 diabetes. Ultimately, the three scientists would like to understand the problems leading to Type 1 diabetes in order to be able to suggest new strategies for treatment as well as prevention.

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Xenotransplantion Examined as Possible Therapy for Diabetes Patients
 Type 1 (insulin-dependent) diabetes is one of the most prevalent chronic diseases among children in The United States. Insulin injection is the basic treatment with pancreatic transplants being performed as more advanced treatment. To fully recover from a pancreatic transplant, a patient must take at least two weeks in the hospital and another three months at home. A much less invasive and safer alternative involves injecting "islet" cells isolated from the pancreas into the patient. In this experimental procedure, a team of doctors removes the pancreas from the donor and insufflates it with collagenase, a proteolytic enzyme. They then supervise a controlled digestion of the pancreas that releases the islets. Then, the islets are delivered via a single injection into the liver. It is a much faster and less invasive procedure and the patient"s recovery time is quicker than in the whole organ transplant.

Pancreatic islet transplantation has the potential to make a huge difference in the future because there are far more diabetes patients than there are pancreata and if pancreatic islets could be recovered from another source, many more patients could be treated. According to TSRI associate professor Daniel R. Salomon, M.D., the best short term bet for developing a clinically viable therapy appropriate for treating tens of thousands of patients in the next five to ten years is to use animals as the source of the islets. Pig insulin works very well in human patients and has been used for many years. Type 1 diabetes afflicts about 1.5 to 1.8 million Americans, and accounts for 30,000 newly diagnosed cases each year. But only about 5,000 whole pancreata are available for transplantation in a given year. Thus, xenotransplantation is a good direction to go in, provided the dangers of risk infection and risk of rejection are overcome.

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Improving the Outcome of an Emerging Therapy for Diabetes
 TSRI Professor John H. Griffin, Ph.D. has collaborated on a paper with Dr. Juan Contreras of the University of Alabama which shows that a compound known as activated protein C or APC greatly improves the outcome of islet transplantation, an emerging therapy for treating diabetes. This published study involves a mouse model of diabetes and of islet transplantation for treating diabetes.

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Effectively Treating Diabetic Retinopathy
 TSRI Associate Professor Martin Friedlander, M.D., Ph.D., has had a longstanding research program looking for new and better ways of treating eye diseases such as diabetic retinopathy, age-related macular degeneration, and retinitis pigmentosa. Friedlander and several other investigators at TSRI were awarded with a $9.6 million National Eye Institute (NEI) grant, titled Fragments of TrpRS to Treat Neovascular Eye Disease. The vast majority of diseases that cause catastrophic vision loss do so as a result of abnormal vessel growth in the back of the eye. In patients under the age of 65, the leading cause of vision loss is due to a complication of diabetes known as diabetic retinopathy. Some 16 to 18 percent of the U.S. population has diabetes. Virtually every one of those patients will eventually have a form of diabetic retinopathy after 20 years, and every year 40,000 of them will lose vision.

Both macular degeneration and diabetic retinopathy are characterized by angiogenesis, or the development of abnormal blood vessel growth in the eye. In diabetic retinopathy, abnormal vessels grow on top of the retina. The vessels interfere with normal structures or the transmission of light to the back of the eye, impeding vision. There is currently no effective treatment for the vast majority of these patients. One of the more promising anti-angiogenic compounds in clinical trials is TrpRS, the one the TSRI researchers will be developing with NEI funding. While 20 to 40 percent inhibition of new vessel formation is typical for the compounds that are in clinical trials, pre-clinical studies on TrpRS have seen 70 to 100 percent inhibition. One clinical approach to treating angiogenic vision loss could be to deliver the TrpRS molecules directly into the eye through gene- and cell-based vectors.

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Study Reveals Unusual Structure Of Cellular Transport Nanocage
 A new study by scientists at The Scripps Research Institute has revealed for the first time the structure of Sec13/31, a "nanocage" that transports a large body of proteins from the endoplasmic reticulum (ER), which makes up more than half the total internal cell membrane, to other regions of the cell. The newly uncovered structure of the Sec13/31 cage reveals a self-assembling nanocage that to a significant degree helps shape basic human physiology from birth to death, and could one day lead to new treatment approaches to a number of diseases including diabetes and Alzheimer"s disease. This new knowledge will allow further study of the structure"s function in building and maintaining membranes required for exporting key molecules such as insulin, involved in the onset of diabetes, and beta amyloid, associated with Alzheimer"s disease. TSRI Professor William E. Balch, Ph.D., led the study. One-third of the proteins encoded by the genome flow through this transport cage. These proteins ultimately control all aspects of cell structure, differentiation, signaling, and proliferation-and when defects occur during transport, the result may be any one of several serious disorders. Expanding our knowledge of this cage structure is fundamental to our understanding of the organization and function of the membrane architecture of every cell in the human body and eukaryotic cells in general. In some ways, our understanding the structure of the nanocage provides a similar level of insight to function in cell biology as the structure of DNA provided key insight into the genetic code.

The results show that the function of Sec13/31 is analogous to that of clathrin, another cellular protein that can also self-assemble in vitro to form transport cages. However, these are strikingly different from the Sec13/31 cage. Balch"s discovery that the self-assembling properties of Sec13/31 produce a unique nanocage structure offers an unprecedented opportunity to study what are most likely novel biological mechanisms underlying cargo selection, concentration and transport of the proteins that pass through this cellular architecture. This may help point the way toward new therapeutic approaches to a variety of diseases. Type II diabetes, amyloidosis, cystic fibrosis, childhood emphysema, and even cancer are caused by protein folding/packaging defects in the ER that result in either a loss of activity or a protein build up in the cell. One focus of Balch"s laboratory has been to understand how these folding defects affect normal protein function within the transport pathway. Through their structural knowledge of the nanocage, they hope to gain critical insight into the basis of several inherited transport diseases. With it, they can begin to delve more deeply into the basic functions of these cargo selection and trafficking pathways. From there, they might be able to develop small molecule chemical modulators to encourage export and stability of misfolded proteins which may lead to restoring normal cellular function in these diseases.

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Study Uncovers New Sensor - A Potential Target For New Therapies For Obesity And Diabetes, And Implications For Heart Disease And Stroke
In a new study, scientists at The Scripps Research Institute and the Genomics Institute of the Novartis Research Foundation (GNF) have described for the first time a glucose activated sensor that acts as a switch to decrease production of endogenous glucose in the liver, and increase conversion of glucose to fat for storage in adipose tissue. This dual action makes the sensor, Liver X Receptor, a potential target for new therapies aimed at obesity and diabetes. The research may also have implications for heart disease and stroke. In the study, glucose is shown to stimulate the activity of the Liver X Receptors (LXR) a and b. The LXRs act as sensors of dietary components, orchestrating the body's response to nutrients such as oxysterols (short-lived derivatives of cholesterol) and controlling gene expression linked to cholesterol and fat metabolism. When you eat, glucose pours into the gut and is recognized by LXR in the liver, which then activates expression of the enzymes that turn excess glucose into triglycerides that are stored as fat. The fact that the study demonstrates that LXR does both - it binds to glucose and it induces fatty acid synthesis - is significant and makes LXR a potential target for diabetes and obesity treatments. Scripps Research Assistant Professor Enrique Saez, Ph.D., led the study

In some recent animal studies, activation of LXRs using synthetic molecules also induced regression of atherosclerosis, the clogging, narrowing, and hardening of the body's large arteries and blood vessels that can lead to stroke, heart attack, and eye and kidney problems. Elevated levels of pathogenic cholesterols, also known to bind LXR, are a primary risk for development of atherosclerosis. The integration of glucose sensing and control of lipogenesis by LXR may explain why low-fat/high-carbohydrate diets induce hypertriglyceridemia [an elevated level of triglycerides in the blood]. LXR can sense surplus glucose, induce fatty acid synthesis, and prompt the liver's export of triglycerides into the bloodstream. Since LXR acts as the body's sensor of a buildup of pathogenic cholesterol, its ability to bind both glucose and oxysterols suggests that LXR may be a link between hyperglycemia and atherosclerosis. In fact, Saez and his colleagues originally looked at LXR as a drug target for atherosclerosis. But when they fed synthetic LXR ligands to mice to induce activation, they discovered that the mice metabolized glucose more effectively and that activation suppressed new production of glucose in the liver.

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